Mutant HSPB1 overexpression in neurons is sufficient to cause age-related motor neuronopathy in mice
Autor: | Nicole E. Naiman, Samantha R. Renusch, Shuping Gu, Zarife Sahenk, W. David Arnold, Stephen J. Kolb, Amit K. Srivastava, Amita Sneh |
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Rok vydání: | 2012 |
Předmět: |
Nervous system
Aging Pathology medicine.medical_specialty animal structures Transgene HSP27 Heat-Shock Proteins Axonal degeneration Mice Transgenic Charcot–Marie–Tooth disease Biology Neuroprotection Article lcsh:RC321-571 Mice Random Allocation Prion protein promoter Charcot-Marie-Tooth Disease Heat shock protein medicine Animals Humans Motor Neuron Disease lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry Heat-Shock Proteins Motor Neurons Neurofilament cytoskeleton Hereditary motor neuropathy Motor neuron Spinal cord Axons medicine.anatomical_structure Gene Expression Regulation Neurology Mutation Peripheral nerve injury Neuroscience Small heat shock protein Molecular Chaperones |
Zdroj: | Neurobiology of Disease, Vol 47, Iss 2, Pp 163-173 (2012) |
ISSN: | 0969-9961 |
DOI: | 10.1016/j.nbd.2012.03.035 |
Popis: | The small heat shock protein HSPB1 is a multifunctional, α-crystallin-based protein that has been shown to be neuroprotective in animal models of motor neuron disease and peripheral nerve injury. Missense mutations in HSPB1 result in axonal Charcot–Marie–Tooth disease with minimal sensory involvement (CMT2F) and distal hereditary motor neuropathy type 2 (dHMN-II). These disorders are characterized by a selective loss of motor axons in peripheral nerve resulting in distal muscle weakness and often severe disability. To investigate the pathogenic mechanisms of HSPB1 mutations in motor neurons in vivo, we have developed and characterized transgenic PrP-HSPB1 and PrP-HSPB1(R136W) mice. These mice express the human HSPB1 protein throughout the nervous system including in axons of peripheral nerve. Although both mouse strains lacked obvious motor deficits, the PrP-HSPB1(R136W) mice developed an age-dependent motor axonopathy. Mutant mice showed axonal pathology in spinal cord and peripheral nerve with evidence of impaired neurofilament cytoskeleton, associated with organelle accumulation. Accompanying these findings, increases in the number of Schmidt–Lanterman incisures, as evidence of impaired axon–Schwann cell interactions, were present. These observations suggest that overexpression of HSPB1(R136W) in neurons is sufficient to cause pathological and electrophysiological changes in mice that are seen in patients with hereditary motor neuropathy. |
Databáze: | OpenAIRE |
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